User:Laura Fountain/Chloride Ion Channel

CLIC1: A Chloride Ion Channel
The CLIC family consists of seven members: CLIC1-5, p64, and parchorin. CLIC1 is the most commonly studied member of the CLIC family because it is expressed to some extent in most tissues and cell types that have been studied and is particularly highly expressed in muscle. Along with being present in the plasma membrane, CLIC1 has been found in various intracellular membranes, such as those of the mitochondria, nucleus (where it is designated NCC27), vesicles, and the endoplasmic reticulum.

This wide range of locations in the cell causes a plausible reason to assume that the CLIC chloride channel family participate in an equally wide variety of physiological processes. Some of these include cell division, kidney function, bone resorption, transepithelial transport, and signal transduction.

CLIC1 is a member of the highly conserved class of chloride ion channels that exist in both soluble and integral membrane forms. When disrupted cells are washed approximately half of the CLIC1 proteins will remain within the fractioned membrane as would be expected from an integral membrane protein. Atypically, the other half will behave as a soluble cytoplasmic protein and exist within the aqueous extract. Tulk et. al. showed that functionality of the protein isn't greatly effected by the method with which the protein inserts itself into the membrane.

This is part of the evidence which leads Tulk et. al. to postulate that CLIC1 is among the small group of proteins which are assembled as soluble cytoplasmic proteins, which will then insert themselves into the appropriate membrane via their own mechanism.

Structure


The CLIC family is defined by a COOH-terminal core segment of ~230 amino acids that are highly conserved among the family members. CLIC1 only contains a few amino acids upstream of the conserved core.

It has a homodimeric structure with one pore per subunit, which creates an incredibly unique "double barreled" channel. The N-domain of CLIC1 (~ amino acids 1-90) consists of 4 beta-sheets and 3 alpha-helices, and the C-domain consists entirely of alpha-helices. The long loop between helices at the foot of CLIC1 (Pro147–Gln164) is a distinctive feature of the CLICs. It is highly negatively charged with seven acidic residues.

Integration of CLIC1 into the membrane is a highly prospect mechanism, but it is likely to require a major structural rearrangement, probably of the N-domain, which would insert itself and then allow the C-domain helices to insert and form the pore.

Selectivity for Chloride
Based on the similarity of CLIC1's antiparallel alpha helical loop (residues 101-145) to those of other better understood proteins which are able to insert themselves into the membrane, Tulk et. al. propose that this is the single area of the protein which is able to transverse the membrane and also serve as a pore. The 5 positively and 5 negatively charged amino acids on each end of the alpha helices could be part of the ion selectivity of this channel.

Potential Ion Gating
At its binding site in the pore, chloride could interact with the ends of four helices that come from both sides of the membrane. A glutamate residue that protrudes into the pore is proposed to participate in gating due to its negative charge.